The Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 91904, Israel.
The Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 91904, Israel.
Stem Cell Reports. 2021 Oct 12;16(10):2520-2533. doi: 10.1016/j.stemcr.2021.09.002. Epub 2021 Sep 30.
Genomic imprinting is a parent-of-origin dependent monoallelic expression of genes. Previous studies showed that conversion of primed human pluripotent stem cells (hPSCs) into naive pluripotency is accompanied by genome-wide loss of methylation that includes imprinted loci. However, the extent of aberrant biallelic expression of imprinted genes is still unknown. Here, we analyze loss of imprinting (LOI) in a large cohort of both bulk and single-cell RNA sequencing samples of naive and primed hPSCs. We show that naive hPSCs exhibit high levels of non-random LOI, with bias toward paternally methylated imprinting control regions. Importantly, we show that different protocols used for the primed to naive conversion led to different extents of LOI, tightly correlated to FGF signaling. This analysis sheds light on the process of LOI occurring during the conversion to naive pluripotency and highlights the importance of these events when modeling disease and development or when utilizing the cells for therapy.
基因组印迹是一种依赖于亲本来源的单等位基因基因表达。先前的研究表明，诱导多能干细胞（hPSCs）向原始多能性的转化伴随着包括印迹基因座在内的全基因组去甲基化。然而，印迹基因异常双等位基因表达的程度仍不清楚。在这里，我们分析了大量原始和诱导 hPSC 的批量和单细胞 RNA 测序样本中的印迹丢失（LOI）。我们表明，原始 hPSC 表现出高水平的非随机 LOI，偏向于父系甲基化的印迹控制区。重要的是，我们表明，用于原始到原始转化的不同方案导致不同程度的 LOI，与 FGF 信号紧密相关。这种分析揭示了在向原始多能性转化过程中 LOI 发生的过程，并强调了在疾病和发育建模或利用细胞进行治疗时，这些事件的重要性。
